Dimethylcyclohex-3-ene-1-carbaldehyde

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

24.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

18

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

440 mg/m³

Explanation for the modification of the dose descriptor starting point:

The overall NOAEL for systemic toxicity is 500 mg/kg bw. The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) advocates a default factor of 2 in case of oral to inhalation extrapolation. The respiratory volume of rats (0.38 m³/kg bw) is multiplied by the respiratory volume of human (6.7 m³/person) and corrected for the respiratory volume for light activity to address the workers (10 m³/person). Therefore, the modified dose descriptor is calculated as follows:500 mg/kg bw / 2 / 0.38 x (6.7/10) = 440 mg/m³

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the OECDTG421 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied to extrapolate the NOAEL from sub-acute to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012)

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOAEC mg/m³, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

3

Justification:

An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR110, 2010). The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients; this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]- response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

72

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8. In the route to route extrapolation for the dermal route no correction is applied because the default absorption of 50% as in the ECHA guidance is used for oral and dermal absorption.

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the OECDTG421 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied to extrapolate the NOAEL from sub-acute to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012)

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling a factor of 4 is applicable to convert rat to human data (ECHA’s guidance, Table R.8-3, 2012).

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

3

Justification:

An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 163 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor:

other: NOEL

Value:

1 163 µg/m³

AF for dose response relationship:

1

Justification:

For the LLNA study an assessment factor of 1 is applicable, because 1) the NOEC is used as a starting point; 2) the doses were well separated (1, 2.5, 5, 10 and 25 %) and; 3) Based on the dose-response in the lower concentrations range an accurate conclusion can be drawn (stimulation index was 2.1, 2.0, 2.9 and 4.2% for 1, 2.5, 5 and 10%, respectively). The absence of a stimulation index above 3 at the top dose does not influence the conclusion.

AF for differences in duration of exposure:

1

Justification:

An assessment factor of 1 is applicable, because the LLNA is considered to be sufficiently sensitive for assessing skin sensitization; 1) considering presence and absence of skin sensitization and; 2) determining a quantitative value for risk characterization (see note 17 in R.8, Application of AFs to the correct starting point to obtain the induction specific DNEL, page 125, 1st par).

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor for allometric scaling is not needed because metabolic rate differences between mouse and human are not expected to be important for the skin sensitization of this substance, because the parent substance is responsible for the effect.

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

1

Justification:

An AF for intraspecies can be reduced.
In this case, an HRIPT test in healthy volunteers is available, which presents a NOEC of 7444 µg/cm2 (200000 µg (200 µl) *0.01 (fraction in the applied dose)/0.25 (25 mm2 is the applied area)*0.9305 (density), which is clearly more than 3 times higher than the NOEC found in the LLNA (1163 µg/cm2). Workers are a similar population compared to the healthy volunteers in the HRIPT study. By using the much lower NOEC from the LLNA as the basis for the DNEL, combined with the existing intraspecies variation in the human population tested in the HRIPT study, the possible influence of intraspecies variation is already sufficiently accounted for and an AF for intraspecies is not needed.

Reference for converting the 1% application concentration in an HRIPT towards ug/cm2: Politano, V.T. and Api, A.M., 2008, The Research Institute for Fragrance Materials' human repeated insult patch test protocol. Regul Toxicol Pharmacol., 52, 35-38.

AF for the quality of the whole database:

1

Justification:

An assessment factor for the quality of the database is not needed because a well-conducted LLNA guideline study is available

AF for remaining uncertainties:

1

Justification:

An assessment factor for remaining uncertainties is not needed. For vehicle effects: an assessment factor of 1 is applied as the matrices of the substance are not intended to enhance penetration. For type of skin (skin thickness and skin integrity) it can be seen that the skin of the back of the human volunteer and the skin of the mouse ear are considered sufficiently similar and more sensitive, respectively, compared to the exposed hands of the worker/consumer. Therefore an AF is not needed.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

The DNELs for long term exposure (systemic effects) were derived in accordance with the Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health with the exception of two assessment factors:

1.        Interspecies differences, remaining differences. For remaining differences it is considered that those already have been taken into account when applying an assessment factor for allometric scaling. The argumentation for this can be found in the ECETOC Guidance on Assessment Factors to Derive a DNEL (Technical Report No. 110, 2010). It is concluded that the concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans. As the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. Thus, this additional variability represented by the GSD of 2.5-2.6 is probably due to not only potential differences in biological sensitivity between species, but also intraspecies differences. The intraspecies variability in humans is taken into account by the specific Assessment Factors for workers (3) and the general population (5). The introduction of the ‘remaining’ AF of 2.5 for interspecies variability would therefore mean an unjustified compilation of AF. Therefore, although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.

2.        Intraspecies differences. The current proposed AF for intraspecies extrapolation of systemic effects for workers and the general population in the ECHA guidance differ from those proposed in the ECETOC guidance (2010). After studying both guidances it is concluded that the AF proposed by ECETOC are based on an evaluation of the scientific literature while the REACH TGD refers to standard default procedures. Therefore, the ECETOC guideline will be followed until the scientific basis for using an alternative approach has been established. This means that for workers instead of an AF of 5 as proposed in the ECHA guidance an AF of 3 will be used and for the general population instead of an AF of 10 and AF of 5.

 

ECETOC, 2010, http://www.ecetoc.org/wp-content/uploads/2014/08/ECETOC-TR-110-Guidance-on-assessment-factors-to-derive-a-DNEL.pdf

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.25 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

217 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL in the OECD TG 407 study is 500 mg/kg bw. The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) advocates a default factor of 2 in case of oral to inhalation extrapolation. In the route to route extrapolation via the inhalation route a correction for respiratory volume is applied by using 1.15 m³/kg bw (ECHA’s guidance R.8, November, 2012). Therefore, the modified dose descriptor is 500 / 2 / 1.15 = 217 mg/m³

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the OECDTG421 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied to extrapolate the NOAEL from sub-acute to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012).

AF for interspecies differences (allometric scaling):

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

5

Justification:

An assessment factor of 5 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, but includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation.

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the OECDTG421 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied to extrapolate the NOAEL from sub-acute to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling a factor of 4 is applicable to convert rat to human data (ECHA’s guidance, Table R.8-3, 2012).

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The value has been derived for systemic toxicity. In view of the systemic component of skin sensitisation the assessment factor can be used for skin sensitisation too.The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

5

Justification:

An assessment factor of 5 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, but includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

582 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor:

other: NOEL

Value:

1 163 µg/m³

AF for dose response relationship:

1

Justification:

For the LLNA study an assessment factor of 1 is applicable, because 1) the NOEL is used as a starting point; 2) the doses were well separated (1, 2.5, 5, 10 and 25 %) and; 3) Based on the dose-response in the lower concentrations range an accurate conclusion can be drawn (stimulation index was 2.1, 2.0, 2.9 and 4.2% for 1, 2.5, 5 and 10%, respectively). The absence of a stimulation index above 3 at the top-dose does not influence the conclusion.

AF for differences in duration of exposure:

1

Justification:

An assessment factor of 1 is applicable, because the LLNA is considered to be sufficiently sensitive for assessing skin sensitization; 1) considering presence and absence of skin sensitization and; 2) determining a quantitative value for risk characterization (see note 17 in R.8, Application of AFs to the correct starting point to obtain the induction specific DNEL, page 125, 1st par).

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor for allometric scaling is not needed because metabolic rate differences between mouse and human are not expected to be important for the skin sensitization of this substance, because the parent substance is responsible for the effect.

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The value has been derived for systemic toxicity. In view of the systemic component of skin sensitisation the assessment factor can be used for skin sensitisation too.The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

2

Justification:

An AF of 2 will be applied for intraspecies differences. In a study by ECETOC (TR 110, 2010), based on scientific literature, it was analysed that an appropriate intraspecies factor for systemic effects for the general population is 5. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.
In this case, a HRIPT test in healthy volunteers is available, which presents a NOEC of 74440 µg/cm2 (200000 µg (200 µl) *0.01 (fraction in the applied dose)/0.25 (25 mm2 is the applied area)*0.9305 (density), which is clearly more than 3 times higher than the NOEC found in the LLNA (1163 µg/cm2). Workers are a similar population compared to the healthy volunteers in the HRIPT study. According to ECETOC (TR110, 2010) the AF for intraspecies differences in the general population is approximately a 2-fold higher compared to workers and consequently healthy volunteers. Consequently, to account for the differences between healthy volunteers and general population, an AF of 2 remains.

Ref: Politano, V.T. and Api, A.M., 2008, The Research Institute for Fragrance Materials’ human repeated insult patch test protocol. Regul Toxicol Pharmacol., 52, 35-38.)

AF for the quality of the whole database:

1

Justification:

An assessment factor for the quality of the database is not needed because a well-conducted LLNA guideline study is available

AF for remaining uncertainties:

1

Justification:

An assessment factor for remaining uncertainties is not needed. For vehicle effects: an assessment factor of 1 is applied as the matrices of the products compiled from the substance are not intended to enhance penetration. For type of skin (skin thickness and skin integrity) it can be seen that the skin of the back of the human volunteer and the skin of the mouse ear are considered sufficiently similar and more sensitive, respectively, compared to the exposed hands of the worker/consumer. Therefore an AF is not needed.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the OECDTG421 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).

AF for differences in duration of exposure:

6

Justification:

An assessment factor of 6 has been applied to extrapolate the NOAEL from sub-acute to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling a factor of 4 is applicable to convert rat to human data (ECHA’s guidance, Table R.8-3, 2012).

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The value has been derived for systemic toxicity. In view of the systemic component of skin sensitisation the assessment factor can be used for skin sensitisation too. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

5

Justification:

An assessment factor of 5 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, but includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

The DNELs for long term exposure (systemic effects) were derived in accordance with the Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health with the exception of two assessment factors:

1.        Interspecies differences, remaining differences. For remaining differences it is considered that those already have been taken into account when applying an assessment factor for allometric scaling. The argumentation for this can be found in the ECETOC Guidance on Assessment Factors to Derive a DNEL (Technical Report No. 110, 2010). It is concluded that the concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans. As the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. Thus, this additional variability represented by the GSD of 2.5-2.6 is probably due to not only potential differences in biological sensitivity between species, but also intraspecies differences. The intraspecies variability in humans is taken into account by the specific Assessment Factors for workers (3) and the general population (5). The introduction of the ‘remaining’ AF of 2.5 for interspecies variability would therefore mean an unjustified compilation of AF. Therefore, although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.

2.        Intraspecies differences. The current proposed AF for intraspecies extrapolation of systemic effects for workers and the general population in the ECHA guidance differ from those proposed in the ECETOC guidance (2010). After studying both guidances it is concluded that the AF proposed by ECETOC are based on an evaluation of the scientific literature while the REACH TGD refers to standard default procedures. Therefore, the ECETOC guideline will be followed until the scientific basis for using an alternative approach has been established. This means that for workers instead of an AF of 5 as proposed in the ECHA guidance an AF of 3 will be used and for the general population instead of an AF of 10 an AF of 5.

 

ECETOC, 2010,http://www.ecetoc.org/wp-content/uploads/2014/08/ECETOC-TR-110-Guidance-on-assessment-factors-to-derive-a-DNEL.pdf